Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes.
Modifying the length of the Huntington's disease (HD) CAG repeat, the major determinant of age of disease onset, is an attractive therapeutic approach. To explore this we are investigating mechanisms of intergenerational and somatic HD CAG repeat instability. Here, we have crossed HD CAG knock-in mice onto backgrounds deficient in mismatch repair genes, Msh3 and Msh6, to discern the effects on CAG repeat size and disease pathogenesis. We find that different mechanisms predominate in inherited and somatic instability, with Msh6 protecting against intergenerational contractions and Msh3 required both for increasing CAG length and for enhancing an early disease phenotype in striatum. Therefore, attempts to decrease inherited repeat size may entail a full understanding of Msh6 complexes, while attempts to block the age-dependent increases in CAG size in striatal neurons and to slow the disease process will require a full elucidation of Msh3 complexes and their function in CAG repeat instability.
Dragileva
Ella
E
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston MA 02114, USA.
Hendricks
Audrey
A
Teed
Allison
A
Gillis
Tammy
T
Lopez
Edith T
ET
Friedberg
Errol C
EC
Kucherlapati
Raju
R
Edelmann
Winfried
W
Lunetta
Kathryn L
KL
MacDonald
Marcy E
ME
Wheeler
Vanessa C
VC
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D003433:Crosses, Genetic; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D042822:Genomic Instability; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
D004268:DNA-Binding Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C089762:Msh3 protein, mouse; C102997:Msh6 protein, mouse; D000074081:MutS Homolog 3 Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; C501002:Xpc protein, mouse; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein